Utilization of complementary and alternative medicine (CAM) by women with breast cancer or gynecological cancer

Background Complementary and Alternative Medicine (CAM) has become increasingly popular among cancer patients. The prevalence of CAM use differs worldwide and depends on different sociodemographic and medical characteristics. Findings on predictors for CAM use and its benefits for quality of Life (QoL) have been inconclusive in recent studies. Objective The aim of the study was to determine the prevalence and methods of CAM use in breast cancer (BC) and gynecological cancer (GC) patients, to compare CAM users vs. non-CAM users regarding their sociodemographic and medical characteristics, and to investigate the relationship between CAM use and QoL. Methods In a sub-analysis from a multicenter, cross-sectional study in Germany, we examined 1,214 female cancer patients (897 with BC and 317 with GC). We obtained data from self-reports via standardized questionnaires and measured QoL with the EORTC QLQ-C30. Results In total, 565 of the 1,214 patients (46.5%) used some form of CAM. Its use was higher in BC than in GC patients (48.6% vs. 40.7%). In both cancer groups, the users evaluated CAM as being helpful (BC: 60.8%, GC: 59.6%) The most frequently used CAM methods were vitamins/minerals/micronutrients, homeopathy, and mistletoe therapy. CAM users are younger, more highly educated, and financially better off than non-CAM users. They are also characterized by having been diagnosed with cancer a longer time ago, being at more advanced stages of the disease, and experiencing higher distress levels. CAM use is significantly associated with a lower global health status/ QoL in GC patients. Predictors for CAM use are: high level of vocational education, middle or high monthly income, time span since diagnosis of more than 12 months, the status of currently ongoing chemotherapy or hormone therapy treatment, and distress. Conclusion Our data support the findings of previous studies and highlight the need to develop a consistent CAM definition with respect to comparability and evaluation of CAM services. More longitudinal studies are desirable to establish viable associations between CAM use and relevant outcomes such as QoL or disease management.

1. natural products such as herbs, vitamins, minerals, and supplements, 2. mind-body practices such as yoga, meditation, and acupuncture, and 3. complementary approaches such as Traditional Chinese Medicine (TCM), Ayurveda, and homeopathy [5].
Worldwide, the most popular CAMs among cancer patients in general are natural products of various plant and processed types, as well as vitamins and minerals [6]. The products used depend strongly on the region. In Arab countries, for example, the preferred CAMs tend to be religious in nature, such as prayers and recitation of the Quran [15,19]. In European countries, vitamins and minerals are most common in BC patients, as well as relaxation methods, homeopathy, and mistletoe therapy [7,9]. In GC patients, herbal medicine, vitamins and minerals are favored [12]. Several CAMs are often used together or successively [8,10,13,16]. With regard to satisfaction with the CAM offers, a high mean satisfaction (60%) was shown in BC and GC patients [8,20].

Association between CAM use and QoL in BC and GC patients
The recording of QoL scores to determine symptom burden is of central importance, especially in cancer patients. Most studies investigating the relationship between CAM use/nonuse and QoL in BC and GC patients show no significant difference in global QoL in both BC [10,16,18] and GC patients [14,21]. However, in many of these studies, significant relationships were found in the QoL scores for various individual items and subscales [14,18]. For example, a review by Smits et al. (2015) showed a significant improvement in fatigue, as well as sleep quality and physical functioning in the intervention group (CAM use) compared to the control group in GC patients [21]. Few studies to date have shown improved global QoL with CAM use, such as Albabtain et al. observed in BC patients in Saudi Arabia [15]. A review by Cramer et al. (2017) found that yoga improved health-related QoL and reduced fatigue and sleep disturbances among BC patients, though the effects were only short-term [22].
In summary, the studies point to a high prevalence of use of and satisfaction with CAM among BC and GC patients. The interpretation and evaluation of the previous study results is difficult, mainly due to different definitions of CAM methods. Also, the often small sample sizes allow only very limited comparability and generalization of the results [6].

Aims of this study
The present study investigates the use of CAM services in 1,214 female patients with BC or GC with the following research questions:

Participants and procedures
In this sub-sample analysis, we use data from a large, multicenter, epidemiological, cross-sectional study, the methods of which have been described in more detail elsewhere [23,24]. Patients were recruited while receiving treatment from oncological inpatient clinics at acute care hospitals, specialized outpatient cancer care facilities, and cancer rehabilitation centers across five study centers in Germany (Freiburg, Hamburg, Heidelberg, Leipzig, and Würzburg). Inclusion criteria consisted of being a cancer patient, between the ages of 18-75, with a malignant tumor. Patients across all tumor entities and disease stages were included. All participants provided written informed consent before taking part in the study. Exclusion criteria were: age younger than 18 or older than 75 years, severe cognitive or physical impairment, language barriers. The study complied with the Declaration of Helsinki and was approved by the research ethic committees of the local medical association in each study center.
Of 5,889 eligible patients, 4,020 (68%) agreed to participate in the study (Fig 1). The primary reasons given for non-participation were lack of interest (55%) and symptom burden (33%). In this analysis, we considered only female patients suffering from BC (897 patients) or GC (317 patients, in particular: 79 cervical, 70 endometrial, 131 ovary and fallopian tube, 37 vulva and vagina).

Measures
Sociodemographic data were collected using a standardized questionnaire. Disease-related characteristics were obtained from medical charts.
Assessment of CAM. Participants were classified as CAM users if they had used at least one type of CAM. Use of CAM was captured by the question "Did you use CAM with regard to your cancer (yes/no), and if so, was it helpful (not at all; a little; some; quite a bit; very much)?" CAM users were then asked which types they had used (anthroposophical medicine, Bach-flowers therapy, enzymes, homeopathy, kinesiology, mistletoe therapy, neural therapy, phytotherapy, traditional Chinese medicine/acupuncture, vitamins/minerals/micronutrients, and others).
Quality of Life. Patients' QoL was assessed using the cancer-specific EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30) [25]. This instrument is widely used and has good reliability and validity. It contains 30 items encompassing five functional scales, three symptom scales, a global health status / QoL scale, and six single items. All of the scores and single items range from 0 to 100. A high score for the global health status represents a high QoL, but a high score for a symptom scale or item indicates more problems and higher levels of symptoms. For our analysis, we focused on the three symptom scales (fatigue, nausea/vomiting, and pain), four symptom items (insomnia, appetite loss, constipation, and diarrhea), and the global health status / QoL. Distress thermometer. With the Distress Thermometer (DT), we assessed the global level of distress experienced in the past week on an 11-point visual analogue scale ranging from 0 ("no distress") to 10 ("extreme distress"). This instrument is validated for use in the German language with the recommended cut-off � 5 to detect cancer-related distress [26].

Statistical analysis
Means and standard deviations (SDs) were used to describe the distribution of quantitative data. Absolute and relative frequencies were used to present qualitative data. We analyzed associations between categorical variables using chi 2 -test/ ANOVA and independent t-test, and for continuous variables we used the Pearson correlation coefficient and Fisher's exact test. To identify predictors for CAM use, binary logistic regression analyzes were performed.
Those sociodemographic and medical factors that showed a significant difference in the bivariate analysis were included in the model. To classify the differences in terms of effect sizes, we used the recommendations by Cohen [27] (d � 0.2 small effect, d � 0.5 medium effect, r � 0.8 large effect). A two-sided p < 0.05 was considered statistically significant for all analysis. Statistical analyses were conducted with IBM1 SPSS Statistics 26, and Microsoft Excel 2010.  Table 1, column A. In summary, there were no differences regarding age, vocational education, and monthly income between the cancer groups. By contrast, significant differences were noticed in relationship status (BC 78.3% vs GC 72.3%, p<0.05), occupational situation (BC 49.6% employed, GC 40.8% employed, p<0.003), time since diagnosis (BC 18.2 month vs. GC 11.2 month, p = 0.001), disease stage, past/current treatment, setting, and the distress thermometer (Table 1, column A: sample characteristics).   Fig 3 shows the most frequently used types of CAM in both groups: vitamins/minerals/micronutrients, homeopathy, and mistletoe therapy. In contrast to that, Bach-flowers therapy, kinesiology, and neural therapy were hardly used. There was a statistically significant difference in the use of vitamins/minerals/micronutrients between BC patients and GC patients (BC 41.2% vs GC 30.0%, p<0.001) and in the use of enzymes (BC 11.0% vs GC 4.0%, p<0.001).    Table 1, column B. The likelihood of using CAM is increased in patients with higher educational status (OR = 1.57), middle income in comparison to low income (OR = 1.41), patients undergoing chemotherapy (OR = 1.66), being treated in a rehabilitation unit (OR = 1.58), and with higher distress levels (OR = 1.87). CAM is most likely to be used if the time since diagnosis is more than 12 months (OR = 2.01).

Discussion
In this analysis, we surveyed German BC and GC patients concerning their usage of CAM and related associations with QoL.
The prevalence of CAM use in the total study cohort was 46.5%. This is in line with other surveys of BC and GC patients [20,28,29]. However, there are several studies with higher prevalence rates, the reasons for which are manifold. In a review report [12] with GC patients from the USA, Europe, Israel, China, and Australia, the prevalence rates varied from 40.3% to 94.7%. According to the authors, the reasons for that broad range are: discrepancies in CAM definitions, diverse CAM modalities, varying research methods (self-report, interviews), as well as geographic and cultural differences in combination with varying attitudes of acceptance of CAM [12].
However, recent studies in particular show an increasing acceptance of CAM methods not only among cancer patients but also among practitioners. CAM is being integrated into conventional therapy, and specialized treatment units are being developed in hospitals in many places, a progression that is leading to increases in the prevalence of CAM use [17,30,31]. The difference in prevalence between BC and GC patients in our cohort is statistically significant (BC 48.6% vs GC 40.7%, p<0.015), similar to those observed by Fasching et al. [29] (BC 50.1% vs GC 44.0%, p = 0.058). The authors understood this difference to be due to BC patients belonging to a better organized network and thus having access to more information than GC patients [29]. Paepke et al. also showed a higher CAM use in BC patients (56.7%) compared to GC patients (43.3%), but did not suggest an explanation for why this is the case [32]. They also found that there was a high interest in CAM in the non-user group. In contrast to the well-researched CAM prevalence, there is significantly less evidence on patient satisfaction regarding their CAM use. Our study shows a 60% satisfaction rate with CAM use ("very satisfied" and "satisfied"). These results have also been found at the same level in comparable studies [8,20].
The most popular CAMs in both groups in our study were (1) vitamins/ minerals/ micronutrients, (2) homeopathy, and (3) mistletoe. These rankings are mostly in line with previous studies [7,9,30,31], though our results reflected lower percentages for the use itself [17]. Neural therapy, kinesiology, and Bach-flowers therapy were hardly used. The CAM types/modalities in the studies from different countries and cultures are as varied as the respective prevalence of their use [6], a fact which limits their comparability.
CAM use is dependent on various sociodemographic and medical characteristics. In our study, the following characteristics were statistically significantly associated with CAM use: younger age (< 50 years), higher vocational education, higher monthly income, longer time since diagnosis, more advanced disease stage, treatment with radiotherapy, chemotherapy and hormone therapy, clinical setting (rehabilitation), and higher levels of distress. These  associations are also reported in a number of other studies [6][7][8][9][10]33]. In addition, there are studies that have failed to demonstrate any associations between sociodemographic or medical characteristics of CAM users [13,14,34]. Reasons for this are: frequently small sample sizes, differences in the availability of CAM, costs in different cultural settings and national health care systems. Consistent with previous studies, the following predictors of CAM use we found were: higher education [7,10,11,35], middle or high monthly income [10], time since diagnosis > 12 months [7,8,11].
However, other medical characteristics such as past/current treatment with chemotherapy, in-patient status in a rehabilitation setting, and higher distress levels are also associated with a significantly higher probability of CAM use in our study. Age also differs significantly between CAM users and non-CAM users in the bivariate analysis (p = 0.001). This statistical effect, however, is no longer detectable in the regression analysis, once it is influenced by the parameters of vocational education and distress level. Numerous other studies have demonstrated age as a predictor of CAM [7,18,28,35]. Furthermore, in contrast to our results, other studies have also shown employment status [8] and stage of the disease [10,18] to be predictors of CAM use. Often, however, no predictors of CAM use could be found [31,36]. The CAM users in our study showed significantly lower QoL scores in many areas, i.e. a higher symptom burden compared to the non-users. In particular, these include pain in BC and GC patients, insomnia in BC patients, and fatigue, appetite loss, and diarrhea in GC patients. From a clinical point of view, this could mean that the motive for CAM use is often hope for symptom relief and to have an active way of coping with the disease. This is also supported by the results of Hwang et al., who showed more frequent CAM use in BC patients with greater symptom burden [11]. The global health status / QoL of GC patients was significantly higher in non-CAM users (54.5 vs 47.9, p = 0.01) in our study.
Due to the cross-sectional study design, no causal relationships can be derived here. Ben-Arye et al. examined CAM use at two different time points (baseline and a 6 to 12-week follow-up) and showed that most outcomes improved in the CAM intervention group [37]. Klafke et al. [38] were able to demonstrate improved QoL scores in fatigue, emotional functioning, and dyspnea among BC and GC CAM users at the end of chemotherapy compared to the start of chemotherapy. For BC patients in our study, no difference in global QoL was found between CAM users and non-CAM users, which is consistent with the results of most previous studies [10,14,16,18,21].
What could these findings mean for clinical practice? Patients with breast and gynecological cancers have a broadly common clinical context with regard to diagnostics, therapy and after-care and are mostly treated by the same specialist. Therefore, both cancer types are discussed within the same framework.
The focus on a large patient group within our study demonstrates to which extent CAM methods are used and which differences can be found between the two types of cancer patients. For doctors as well as for clinical staff, it is very important to know which preferences patients have regarding their aftercare within the framework of oncological therapy. It helps all physicians to define and recommend the right additional medical treatment for each patient individually, which can be easily integrated into clinical care plans.
Although the number of studies on CAM use has multiplied over the last 10 years, evidence for the effects of CAM is still very sparse. Above all, longitudinal studies are necessary in order to evaluate causalities and also to derive better dose-response relationships. Adverse effects as well QoL scores respectively should be investigated regularly before, during and after the cancer therapy, preferably by using standardized questionnaires such as the EORTC QLQ-C30 or the QLQ-BR23. This approach would enable the evaluation of and recommendations for the use of CAM methods at a very individualized level. In particular, for the most popular CAM group of vitamins/minerals/micronutrients there are no dose specifications and the application should ideally be monitored by taking blood samples. Our and many other studies have shown that older patients in particular are less likely to use CAM [9,12], yet high BMI and concomitant medication are also associated with a lower interest in integrative medicine. [28]. It represents a vicious circle as old age and high BMI increase the risk of chronic diseases and cancer itself. Furthermore, there a no effective screening strategies for gynecological malignancies such as Ovarian or endometrial cancer as shown in a recent study by Giannini et al [39]. CAM is to be considered here in terms of tertiary prevention in order to achieve the best possible QoL. The population will continue to age in the future, so that an increasing number of older people with comorbidities will be diagnosed with cancer compared to today. CAM use should also enable a strategy to improve the oncological outcome comparable to the preoperative evaluation of the frailty of gynecological cancer patients proposed by D'Oria et al [40].

Limitations and strengths of the study
There were some limitations of our study. First, it was a cross-sectional design and, therefore, no conclusion regarding causality with CAM use can be drawn. Second, we did not ask about participants' motivation for CAM use and non-CAM use, and we did not ask about any previous patterns of CAM use prior to the respondent's cancer diagnosis.
The strengths of this study are its large sample size and the multicenter study design. By including patients in different treatment settings (acute care clinic, outpatient departments, rehabilitation centers), it is possible to examine CAM use throughout the treatment course. Because the methodology is identical, is it possible to directly compare both cancer types.

Conclusion
Though this is not the first study to examine patients with gynecological malignancies and their use of CAM (prevalences, modalities, characteristics, predictors, and associations with QoL), it does underline previous study results, especially in Germany. Creating uniform definitions for CAM and CAM modalities with regard to the comparability of study results is of enormous importance for further research in this area. Likewise, larger longitudinal studies should be conducted in the future to capture causality between CAM use and QoL.

Summary
About half of our study cohort uses CAM, BC more than GC patients, and users are predominantly satisfied with this use. There are sociodemographic and medical predictors of CAM use such as younger age, high educational status, no acute care (or in rehabilitation), and higher distress. In GC patients, CAM use is more often associated with worse QoL.